A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer.

Thrombospondin (TSP)-1, a potent angiogenesis inhibitor, has been shown to exert different biological functions on various cell types. Here, we investigate the role of TSP-1 in tumor-stroma reaction, which is mainly characterized by fibroblast activation to create a permissive microenvironment for tumor progression. Immunohistochemistry examinations in the human surgical specimens have shown that a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, alpha-smooth muscle actin (alpha-SMA) and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited antiangiogenic activity in vitro and resulted in reduced tumor growth in severe combined immunodeficiency (SCID) mice, which was accompanied by a decrease in tumor vascularization and lower expressions of alpha-SMA and desmin than those in the vector controls. Transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of alpha-SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-beta (TGF-beta), a major factor in the activation of fibroblasts, increased alpha-SMA and desmin expression and the ability of cell migration and invasion in NIH3T3 cells. The increased migration ability and the invasive ability into tumor cluster of TGF-beta-treated NIH3T3 cells were dose dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells. Together, our findings demonstrate a novel role of TSP-1 to inhibit tumor-stroma reaction that could be attributed to the blockage of activated fibroblasts from invading cancer cells.